Staphylococcus aureus is a major cause of infectious disease in the United States and in the world. S. aureus can infect almost every human tissue, causing pathologies ranging from minor skin infections to rapidly life- threatening infections, such as necrotizing pneumonia and sepsis. Treatment options for S. aureus infection are dwindling as multidrug resistant strains continue to emerge and to become more common both inside and outside of the hospital. S. aureus has many virulence factors that it uses to evade host immunity and be so successful as a pathogen. One class of these virulence factors is the bi-component pore-forming leukotoxins. These toxins kill host cells by binding to specific protein receptors and forming pores in their cell membranes, lysing the cells. The leukotoxins kill neutrophils, which are key mediators of immunity to acute bacterial infection, and thus help the bacteria to survive during infection. Two of these toxins, LukED and HlgAB, are also capable of killing red blood cells, and recent work has shown that this is accomplished by targeting the DARC receptor. Interestingly, both of these toxins are lethal to mice when administered intravenously. We now aim to investigate the role of the DARC receptor in the activity of these toxins and in S. aureus pathogenesis more fully by pursuing the following aims: (1) Define the mechanism(s) by which LukED and HlgAB are lethal in vivo and the role of DARC and (2) Determine the molecular mechanism by which these toxins target DARC. Together, these studies will advance our understanding of S. aureus pathogenesis and highlight the need to develop novel therapies and vaccines that inhibit the actions of these toxins.